FACTA UNIVERSITATIS

Series: Medicine and Biology Vol.9, No 3, 2002, pp. 201 - 206 UC 615.363

COMPETITIVE INHIBITORS OF ENZYMES

AND THEIR THERAPEUTIC APPLICATION

Gordana Bjelaković, Ivana Stojanović, Goran B. Bjelaković1,

Dušica Pavlović, Gordana Kocić, Angelina Daković-Milić

Institute of Biochemistry, 1Clinic of Hepato-Gastroenterology, Faculty of Medicine, University of Niš, Serbia

Summary. Enzymes catalyze virtually every biochemical process in the cell. The usefulness of the most important
pharmaceutical agents, antimetabolites, is based on the concept of competitive enzyme inhibition. The antimetabolites
are structural analogues of normal biochemical compounds. As competitive inhibitors they compete with the naturally
substrate for the active site of enzyme and block the formation of undesirable metabolic products in the body.
Antibacterial, antiviral and anticancer pharmaceutical agents are among numerous examples of antimetabolites. Sulfa
drags, sulfanilamide, structural analogs of amino acids (cycloserine, L-fluoroalanine), folic acid antagonists (4-
amino-10-methyl folic acid=methotrexate), analogues of purine and pyrimidine (6-mercaptopurine, allopurinol, 5-
fluorouracil, 5-azacytidine), inhibitors of polyamine biosynthesis (difluoromethyl ornithine, methylglyoxal-bis (guanyl
hydrazone)) are the most used in modern chemotherapy The use of enzyme inhibitors, antimetabolites, beside the
therapeutic significance has also provided valuable informations about enzyme mechanisms and has helped to define
some metabolic pathways.
Key words: Enzyme inhibitors, sulfa drugs, antimetabolites, folic acid antagonists, purine and pyrimidine
analogues, polyamines antagonists, chemotherapy

Introduction inhibitor - enzyme interaction enzyme-inhibitor a com-

Enzymes are the reaction catalysts of biological
systems which accelerate and direct specific biochemi-
cal reactions. Great specificity (speciality) of enzymes is
a very important biological phenomen which assures
high coordination to yield a harmonious interplay
among many different metabolic activities necessary to
sustain life.
Modification of enzyme activity
It is well known that activities of intracellulary and
extracellulary enzymes depend on numerous constitu-
ents of medium or circumstances. The most important
factors which influence enzyme activity are presented
by enzyme concentration, the amount of specific en-
zyme substrate, electrochemical reaction of medium for
enzyme activity (pH), the presence of activators (spe-
cific or nonspecific) as well as the presence of inhibitors
(naturaly occuring or intended for specific purpose, co-
monly used as chemotherapeutic agents).
Inhibitors of enzymes
The inhibitors of enzyme activity are chemical sub-
stances, which in small quantity decrease the activity of
enzymes in a specific chemical way. As a result of the
plex is formed: once bound, the enzyme cannot convert
the inhibitor to products. The existence of specific natu-
rally occurring enzyme inhibitors, like antithrombin,
antipepsin and antitrypsin, controls the enzyme activity
in human the body and under physiological circum-
stances assures their intracellular and extracellular ac-
tion. Among the naturally occurring enzyme inhibitors
there are also intermediary products formed during
some metabolic pathways. Product inhibition provides a
limited mean of control or modulation of substrate flux
through the pathway. If one or more enzymes are allo-
steric enzymes particularly sensitive to product inhibi-
tion, the output of end product of the pathway will be
suppressed (1).
Mechanism of competitive
inhibitors action
Competitive inhibitors are compounds that resemble
structurally the substrate and compete with substrate for
the active site of an enzyme to form an enzyme-inhibi-
tor complex. Once the inhibitor occupies the active site
of enzyme it prevents binding of substrate and abolishes
the formation of normal metabolic product (1,2). In-
hibitor binds reversibly the enzyme and because of that
the competition can be decreased simply by adding
more substrate. When enough substrate is present the
202
probability that an inhibitor molecule will be bound is
minimized, and enzyme reaction exhibits a normal Vmax.
In the presence of competitive inhibitor Michaelis-
Menten constant, Km will increase (2).
Application of competitive inhibitors
in medicine
Enzymes catalyze virtually every process in the cell
and it should not be surprising that enzyme inhibitors
are among the most important pharmaceutical agents
known. Classic example of competitive inhibitor of suc-
cinate dehydrogenase is malonic acid / HOOC-CH2 -
COOH /, structural analog of succinic acid/ HOOC-CH2
- CH2 - COOH / (Fig. 1). In the presence of malonic
acid succinate dehydrogenase activity, one of citric acid
cycle enzymes, is inhibited, and the reaction of citric
cycle is blocked, respectively (1-2).
COO
CH2 COO
CH2 CH2
COO COO
Succinate Mallonate
Fig. 1.
Most modern drug therapy is based
on the concept of enzyme inhibition
Competitive inhibition is used therapeutically to
treat patients who have ingested methanol. In the human
body ingested methanol is converted into formaldehyde
by the action of the enzyme alcohol dehydrogenase.
Formaldehyde damages many tissues, and blindness is a
common result because the eyes are particularly sensi-
tive. The therapy of methanol poisoning is intravenous
infusion of ethanol; ethanol competes effectively with
methanol as a substrate for alcohol dehydrogenase.
Ethanol is also substrate for alcohol dehydrogenase
forming acetaldehyde and acetate. Intravenous infusion
of ethanol slows down the formation of formaldehyde
so that most of methanol can be excreted harmlessly by
urine.
The application of therapeutical drugs as a specific
enzyme inhibitors, inhibits the playing of unwanted
metabolic pathways in the body and for that reason
these drugs are named antimetabolites (2). Antibacte-
rial, antiviral and antitumor drugs belong in the group of
this drugs. The administration of those drugs to the pa-
tients causes limited toxicity because there are few criti-
cal metabolic pathways that are unique to tumors, vi-
ruses, or bacteria; hence drugs that kill these organisms
will often kill host cell. Antimetabolites are compounds
with some structural difference from the natural sub-
strate and belong in the group of competitive enzyme
inhibitors. Sulfa drugs, structural analogs of amino ac-
ids, folic acid antagonist, analogs of purines and pyri-
midines belong to this group of enzyme inhibitors.
G. Bjelaković, I. Stojanović, GB. Bjelaković et al.
Application of sulfa drugs in medicine
Modern chemotherapy had its beginning in com-
pounds with the general formula R-SO2 -NHR,. The
simplest member of sulfa drugs is sulfanilamide, an
antibacterial agent. Sulfanilamide is an antibiotic useful
in the treatment of some kidney infection. As a struc-
tural analog of p-aminobenzoic acid (PABA) (Fig. 2),
sulfanilamide inhibits bacterial growth. PABA is a
structural part of folic acid, which is composed of pteri-
dine, p-aminobenzoic acid and glutamic acid. Some
kinds of bacteria require folic acid for their growth and
division. As the structural analog of p-aminobenzoic
acid sulfanilamide is a competitive inhibitor for bacte-
rial dihydrofolate synthetase. Thus bacteria are starved
of the required folate and cannot grow and divide. Sul-
fanilamide is antibiotic useful in the treatment of some
kidney infection. This drug is highly toxic to bacteria
that must synthesize their own folic acid. Since humans
require folate from dietary source, the sulfanilamide is
not harmful at the doses that kill bacteria (2).
O O
H2N C H2N S NH2
O O
p-Aminobenzoate Sulfanilamide
Fig. 2.
Structural analogs of amino acids
Structural analogs of amino acids are used as anti-
bacterial drugs. D-amino acids, like D-alanine and D-
glutamic acid, occur as structural part of bacterial cell
walls and peptide antibiotics. D-Amino acids arise di-
rectly from the L isomers by the action of amino acid
racemases, which have pyridoxal phosphate as a re-
quired cofactor. Racemisation of amino acids is
uniquely important to bacterial metabolism, and enzyme
such as alanine racemase represent prime targets for
pharmaceutical agents. One such agent, L-fluoroalanine
(Fig. 3), is being tested as an antibacterial drug. Cyclo-
serine, analog of serine (Fig. 4), is already used to treat
urinary tract infection and tuberculosis. In modern psy-
chiatry cycloserine is frequently used as a therapeutic
agent (3-5). As a structural analog of serine, cycloserine
inhibits the synthesis of sphingosine, sphingomyelin
respectively (6).
O
COO H 2C NH
H 3N C H
HC C
CH2
H 3N O
F
L-Fluoroalanine Cycloserine
Fig. 3. Fig. 4.
Folic acid antagonists-antifolates
Folic acid, folacin or pteroil glutamic acid belong to
the group of water soluble vitamins. Fresh leafy green
COMPETITIVE INHIBITORS OF ENZYMES AND THEIR THERAPEUTIC APPLICATION
vegetables, cauliflower, kidney and liver are rich sources
of folic acid. The physiological function of folic acid
coenzymes is in the synthesis of purine nucleotides and
thymine, precursors in the synthesis of RNA and DNA
intracellulary, respectively. The folic acid coenzymes are
specifically concerned with biochemical reactions
involving the transfer and utilization of the single carbon
(C1)) moiety. Before functioning as a C1 carrier, folic acid
must be reduced, first to 7,8-dihydrofolic acid (H2 -
folate) and then to the tetrahydro compound (H4 - 5,6,7,8-
tetrahydrofolic acid) catalyzed by folic acid reductase
which uses NADPH as hydrogen donor.The participation
of folic acid coenzymes in reaction leading to synthesis of
purines and to thymine, the methylated pyrimidine of
DNA, emphasizes the fundamental role of folic acid in
the growth and replication of cells. Cancer cells grow
more rapidly than the cells of most normal tissues and
thus they have greater requirements for nucleotides as
precursors of DNA and RNA synthesis. Consequently,
cancer cells are generally more sensitive to inhibitors of
nucleotide biosynthesis than are normal cells.
H2N N
H
N
N pathway; some metabolites of thioguanine are incorpo-
N CH2 O COO
NH2 N C NH CH CH2 CH2
H 3C
Methotrexate
Fig. 5.
The folic acid antagonists, methotrexate and ami-
nopterin, close structural analogs of folic acid, as anti-
tumor agents have found clinical application in the
treatment of malignant diseases, especially in the treat-
ment of leukemia in childhood (7-10). Antifolates, fo-
late analogs, aminopterin (4-amino folic acid) and
methotrexate (amethopterin, 4-amino-10-methylfolic
acid) (Fig. 5) are extremely potent competitive inhibi-
tors of the dihydrofolate reductase and thymidylate
synthetase and because of that inhibits the synthesis of
RNA and DNA. Dihydrofolate reductase enzyme is
needed for the reduction of dihydrofolic acid (DHF) to
tetrahydrofolic acid (THF). Dihydrofolate reductase
binds methotrexate about 100 times better than dihydro-
folate. Thymidylate synthetase uses methyl-tetrahydro-
folic acid as a substrate and transfer methyl group to
uracil present in the deoxyuridinemonophosphate
(dUMP); in this transmethylation reaction deoxythymi-
dinemonophosphate (dTMP), precursor in the biosyn-
thetic pathway of DNA,is formed which represents the
key step in the cell replication and division. Enzyme
dihydrofolate reductase binds methotrexate about 100
time better than dihydrofolate. The development of drug
resistance to methotrexate appears if the chemotherapy
prolongs. Tumor cells that acquired MTX resistances
have been found to have an increased number of DNA
gene copies encoding for enzyme dihydrofolate reduc-
tase. This form of multiple gene reduplication is called gene
amplification The amplified DHFR genes in MTX-resis-
tance cells produce a markedly increased number of copies
203
of DHFR enzyme, for exceeding the amount of MTX that
can be delivered to cell, and thereby allows tumor cell DNA
synthesis and tumor regrowth occurrs (11).
The application of methotrexate distrurbs the
metabolism of polyamines in rapidly growing tissues.
Inhibition of polyamine oxidase, the key enzyme in bio-
degradation pathway of spemine and spermidine, in-
duced by methotrexate in regenerating rat liver tissue
(12) is probably the consequence of the inhibition of
nucleic acids and protein synthesis.
Structural analogs of purine and
pyrimidine
6-mercaptopurine (6-MP), the analog of hypoxan-
thine and adenine (Fig. 6), is a useful antitumor drug in
humans. In the C6 position of purine ring of hypoxan-
thine or adenine instead of NH 2 or OH group 6-MP has
SH group (1,2). 6-thioguanine (6-TG) is also thio-pu-
rine, analog of guanine. Both thioguanines, 6-MP and 6-
TG are converted to nucleotide form by hypoxanthin-
guanine phosphoribosyl transferase (HGPRT): their
meabolites inhibit a number of enzymes in the purine
COO
rated into both DNA and RNA (16, 18). By incorpora-
tion and inhibition of nucleic acid synthesis this thio-
guanine is pariculary used in hemotherapy of malignant
diseases (10, 13-16). Well known competitive inhibitor
of enzyme, as a therapeutic agens in medicine is allopu-
rinol, administrated to patients who suffer of gout. Gout
is a disease of joints, usually in males, caused by an
elevated concentration of uric acid in blood and tissues.
The precise cause of gout is not known, but it is sus-
pected to be due to genetic deficiency of one or another
enzyme concerned in purine metabolism. The principal
enzyme in this metabolism is xanthine oxidase (2).
SH
N
N
N
N
H
6-Mercaptopurine
Fig. 6.
Allopurinol is structural analog of hypoxanthine
(Fig. 7) and represents a competitive inhibitor of xan-
thine oxidase. When xanthine oxidase is inhibited the
conversion of purines into uric acid is stopped; in this
case the excreted products of purine metabolism are
xanthine and hypoxanthine, which are more soluble in
water than uric acid and less likely to form crystalline
deposits (4).
OH SH
H
N
N C N
N CH
N N N N
H H
Hypoxanthine (enol form) Allopurinol
Fig. 7.
204 G. Bjelaković, I. Stojanović, GB. Bjelaković et al.

5-fluororacil (5-FU) is a thymine analog in which the to cell growth and proliferation (20,21). The key en-
ring bound methyl group is substituted by fluorine zymes in their biosynthesis are ornithine decarboxylase
(Fig. 8). The deoxynucleotide of this compound is an (ODC), which produce putrescine, and S-adenosyl-
inhibitor of thymidilate sunthetase. 5-FU undergoes methionine decarboxylase which is involved in sper-
biotransformation to ribosyl and deoxyribosil nucleotide midine and spermine synthesis (22). Structural analogs
metabolites. 5-fluorouridine triphosphate is incorporated of ornithine α -methyl ornithine (Fig. 10) and difluo-
in RNA and interferes with RNA processing and function. romethyl ornithine (Fig. 11) are the most used competi-
O
tive inhibitors (23-25).
F F
F
HN CH3 CH O
H 2N CH2 CH2 CH2 C COOH H2N CH2 CH2 CH 2 C C
O N
H NH2 NH2 O

Fluorouracil Fig 10. α-Methylornithine Fig.11. Difluoro-methylornithine

Fig. 8.
Incorporation of 5-fluorouracil into deoxyribonu-
cleotide, 5-fluorodeoxyuridine monophosphate, results
in irreversible inhibition of enzyme thymidylate sun-
thetase and impossibility of thymidylate (TMP) synthe-
sis. Inhibition of thymidine monophosphate formation
blocks DNA synthesis and cell multiplication (10, 16-
18). 5-FU is an important anitcancer agent in the treat-
ment of different solid tumors.
Cytosine arabinoside, ara-C, also belongs to the
group of pyrimidine antagonists. This nucleoside is a
specific agent of cell division S-phase especially used in
acute nonlymphocyte leukemia therapy and less in the
treatment of other malignant hematologic diseases. In-
tracellularly cytosine arabinoside is metabolised into
active form, ara-CTP, which competitively inhibits
DNA polymerase, thus blocking DNA synthesis (10).
NH2
N N
N O
H OCH 2
O NH
Methyl-glyoxal-bis (guanyl hidrazone), MGBG, in-
hibits activity of S-adenosylmethionine decarboxylase
(SAMDC), the key enzyme in spermidine and spermine
synthesis (26-28). The application of MGBG (Fig.12) as
antiproliferative agent, is used in chemotherapy of ma-
lignant diseases; it is based on the fact that accelerated
polyamine biosynthesis preceedes the accelerated nu-
cleic acid synthesis which provides rapid cell prolifera-
tion. Blockade of polyamine synthesis slows down cel-
lular growth and proliferation of malignant tissues (29).
The new drugs in the treatment of colon cancer are highly
specific and non-toxic hydroxylamine-containing com-
petitive inhibitor of ornithine decarboxylase (ODC) 1-
aminooxy-3-aminopropane (APA), structural analog of
ornithine (Fig.13) and competitive inhibitor of S-ade-
nosyl-methionine decarboxylase (SAMDC), 5,-deoxy-5,-
adenosyl-methylthioethyl-hydroxylamine, (AMA) (Fig.
14), structural analog of S-adenosyl-methionine (30).
This hydroxylamine - containing inhibitors od ODC and
of SAMDC inhibit colon cancer cell proliferation and
might be therapeutically promissing in colon cancer.
H 2N C NH N CH C N NH C NH2
CH3 NH

MGBG
OH OH Fig 12.
5-Azacytidine
H 2N
Fig. 9. O NH2

APA
Another structure analog of cytidine is 5-azacytidine
(Fig. 9). Intracellularly 5-Aza-C is metabolised into 5- Fig. 13. 1-aminooxy-3-aminopropane
aza-CTP afterwhat it is involved in DNA and RNA N
synthesis, damaging protein synthesis. CH3 N NH2
The possibility of application of purine and pyrimidine S O
structural analogs as competitive inhibitors in resembling O N N
nucleotide biosynthesis is not limited only to cancer NH2
treatment. All rapidly growing cells (including bacteria and HO
OH
protozoa) are potentially sensitive to these agents (1).
AMA

Structural analogs of polyamines Fig.14. 5,-deoxy-5,-adenosyl-methylthioethyl-hydroxylamine

as anticancer agents
Polyamines, spermine, spermidine and putrescine
are normal cell constituents. Accelerated biosynthesis
and accumulation of polyamines are directly connected
The application of specific inhibitors of polyamine
biosynthesis or degradation enables more detailed un-
derstanding of polyamine physiological role.
COMPETITIVE INHIBITORS OF ENZYMES AND THEIR THERAPEUTIC APPLICATION
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206 G. Bjelaković, I. Stojanović, GB. Bjelaković et al.

KOMPETITIVNI INHIBITORI ENZIMA I NJIHOVA TERAPIJSKA PRIMENA

Gordana Bjelaković, Ivana Stojanović, Goran B. Bjelaković1,

Dušica Pavlović, Gordana Kocić, Angelina Daković-Milić

Biohemijski Institut,1Klinika za Hepato-Gastroenterologiju, Medicinski Fakultet, Niš

Kratak sadržaj: Enzimi katalizuju gotovo sve biohemijske procese u ćeliji. Primena mnogih lekova u medicini,
antimetabolita, bazirana je na konceptu kompetitivne enzimske inhibicije. Antimetaboliti se veoma malo strukturalno
razlikuju od prirodnih enzimskih supstrata. Svoja specifična dejstva ispoljavaju ponašajući se kao kompetitivni
inhibitori određenih enzimskih reakcija blokirajući formiranje neželjenih metabolita u organizmu.U antimetabolite
spadaju antibakteriski, antivirusni i antitumorski lekovi. Najzastupljeniji od njih jesu sulfonamidi, strukturni analozi
amino kiselina (cikloserin, 5-fluoroalanin), antagonisti folne kiseline (4-amino-10-metil folna kiselina -metotreksat),
analozi purina i pirimidina (6-merkaptopurin, alopurinol, 5-fluorouracil, 5-azacitidin), inhibitori biosinteze poliamina
(α-difluorometil ornitin, metillglioksal-bis (guanil hidrazone=MGBG).
Primena enzimskih inhibitora, antimetabolita,osim terapiskog značaja, omogućava bolje razumevanje raznih
metaboličkih puteva, kao i bolje upoznavanje mehanizma delovanja enzima.
Ključne reči: Enzimska inhibicija, sulfonamidi, antimetaboliti, antifolati, analozi purina i pirimidina,
analozi poliamina, hemioterapija